Skin therapeutics

ABSTRACT

Disclosed herein are methods and compositions for treatment of skin disorders and diseases using botulinum toxin targeted to nerve ganglia. It has been unexpectedly found that botulinum neurotoxin (BoNT) can decrease the severity of numerous skin disorders by application to nerve ganglia including but not limited to the parasympathetic, sympathetic, and sensory ganglia

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/723,742, filed Aug. 28, 2018, and U.S. Provisional Application No.62/918,603, filed Feb. 6, 2019, which applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Acne, eczema, psoriasis, seborrhea, and rosacea are common skindisorders, effective methods for treating these disorders are lacking. Avariety of topical treatments are available, including treatment withbotulinum toxin, but their efficacy is limited.

SUMMARY OF THE INVENTION

Disclosed herein are methods and compositions for treating skindisorders comprising applying a therapeutically effective amount ofbotulinum neurotoxin to nerve ganglia. wherein the nerve ganglia is aparasympathetic nerve ganglia. In some embodiments, the nerve ganglia isa sphenopalatine ganglia, a ciliary ganglia, a submandibular ganglia,superior cervical ganglia, trigeminal ganglia, stellate ganglia and/oran otic ganglia. In other instances, the nerve ganglia is asphenopalatine ganglia. In yet other embodiments, the botulinumneurotoxin is applied to a pterygopalatine fossa. In still otherembodiments, the botulinum neurotoxin is applied to the sphenopalatineganglia. In yet other embodiments, the botulinum neurotoxin is appliedzygomatically, intranasally, through a hard palate technique, using ahigh tuberosity approach or combinations thereof.

In some embodiments, the skin disorder is chosen from the groupconsisting of acne, eczema, psoriasis, seborrhea, rosacea andcombinations thereof In still other instances, the botulinum neurotoxinis chosen from the group consisting of botulinum neurotoxin type A,botulinum neurotoxin type B, botulinum neurotoxin type C, botulinumneurotoxin type D, botulinum neurotoxin type E, botulinum neurotoxintype F, botulinum neurotoxin type G, and combinations thereof. In someinstances, the botulinum neurotoxin type B is administered withepinephrine. In still other instances, the botulinum neurotoxin type Bfurther comprises a basic solution. In other instances, the amount ofbotulinum neurotoxin administered is between about 0.1 to about 1000units. In yet other instances, the amount of botulinum neurotoxinadministered is between about 5 to about 50 units. In still otherembodiments, the botulinum neurotoxin is administered over a period oftime. In yet other embodiments, the botulinum neurotoxin is administeredover one minute. In still other instances, the volume of botulinumneurotoxin administered is between 0.1 to 10 cc. In yet otherembodiments, the botulinum neurotoxin is further administered locally tothe skin.

Disclosed herein are methods and compositions of smoothing skin andreducing wrinkles in skin, the method comprising applying atherapeutically effective amount of botulinum neurotoxin to nerveganglia. In some embodiments, the skin pore size is reduced. In someinstances, the botulinum neurotoxin is chosen from the group consistingof botulinum neurotoxin type A, botulinum neurotoxin type B, botulinumneurotoxin type C, botulinum neurotoxin type D, botulinum neurotoxintype E, botulinum neurotoxin type F, botulinum neurotoxin type G, andcombinations thereof In yet other instances, the botulinum neurotoxintype B is administered with epinephrine. In still other instances, thebotulinum neurotoxin type B further comprises a basic solution.

Disclosed herein are methods and compositions for treating skininfections related to excessive holocrine secretions comprising applyinga therapeutically effective amount of botulinum neurotoxin to nerveganglia. In some embodiments, the excessive holocrine secretioncondition is chosen from the group consisting of hidradenitis,furuncles, carbuncles, styes, chalazions, horoleum and combinationsthereof. In some embodiments, the botulinum neurotoxin is chosen fromthe group consisting of botulinum neurotoxin type A, botulinumneurotoxin type B, botulinum neurotoxin type C, botulinum neurotoxintype D, botulinum neurotoxin type E, botulinum neurotoxin type F,botulinum neurotoxin type G, and combinations thereof. In someembodiments, the botulinum neurotoxin type B is administered withepinephrine. In still other embodiments, the botulinum neurotoxin type Bfurther comprises a basic solution.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

It has been unexpectedly found that botulinum neurotoxin (BoNT) candecrease the severity of numerous skin disorders by application to nerveganglia including but not limited to the parasympathetic, sympathetic,and sensory ganglia. Accordingly, disclosed herein are methods andcompositions for the treatment of skin disorders and diseases byapplication of a therapeutically effective amount of botulinumneurotoxin to nerve ganglia, including the following diseases and alltheir related forms: acne, eczema, psoriasis, rosacea and diseasesrelated to excess holocrine and sebaceous disorders: seborrheicdermatitis, rhinophyma, and sebaceous cysts. Also disclosed herein aremethods and compositions for the treatment of infectious conditions inthe skin related to excessive holocrine secretions include hidradenitis,furuncles, carbuncles, styes, chalazions and horboleum by application tonerve ganglia of a therapeutically effective amount of botulinumneurotoxin. In addition, the application of botulinum neurotoxin tonerve ganglia can cause skin to become smooth, and thus to decreasewrinkling or the appearance of wrinkles in the skin.

Investigators have in the past applied botulinum neurotoxin to treatvarious diseases, including as a topical agent to the skin, but nonehave applied botulinum neurotoxin to nerve ganglia for the treatment ofskin disorders and diseases.

For example, in 1994 Sanders and Shaari (U.S. Pat. No. 5,766,605,Treatment of autonomic nerve dysfunction with botulinum toxin)discovered that BoNT could be used to treat disorders of the autonomicnerves. Indications included rhinorrhea, asthma, and decreasing sweating(hyperhidrosis). In 1995, Binder discovered that injection of BoNT intothe mid face for cosmetic purposes also had a beneficial effect onpsoriasis, dermatitis, and forms of pityriasis (U.S. Pat. No. 5,670,484AMethod for treatment of skin lesions associated with cutaneouscell-proliferative disorders). The mechanism of this improvement wasunknown, however, Binder theorized that these diseases resulted fromexcessive growth of skin cells. The BoNT somehow decreased theproduction of new skin cells.

In 2001, Suskind et al. (U.S. Pat. No. 7,226,605B2 Botulinum toxin inthe treatment or prevention of acne) discovered that injections ofbotulinum toxin can decrease the severity of acne vulgaris. In 2002,Sanders and Aquila discovered that application of botulinum toxin to theskin can decrease sebaceous secretions, thereby treating seborrhea.Unexpectedly, they also found that botulinum toxin decreased rosacea.Moreover, they also discovered that there were cosmetic benefits ofBoNT, specifically smoothing of skin and decrease in fine wrinkles. SeeU.S. Pat. No. 7,288,259 (Treatment of holocrine gland dysfunction withclostridia neurotoxin); U.S. Pat. No. 8,202,522 (Skin cosmesis treatmentwith clostridia neurotoxins).

In 2002, Sanders discovered that application of BoNT to the nose orsphenopalatine ganglion (SPG) decreased all symptoms of allergicrhinitis (sneezing, itching, congestion and rhinorrhea) and asthma (U.S.Pat. Nos. 8,088,360, 9,314,513 8,092,781, 8,349,292, 7,879,340). In2003, Sanders also discovered that botulinum toxin applied to thesphenopalatine ganglion could decrease migraine headaches (U.S. Pat. No.9,504,735). More recently, Bratback et al. confirmed Dr. Sanders'findings by showing that 25 units of botulinum toxin applied bilaterallyto the PPF and SPG can cause a 50% decrease in migraine headaches, and asimilar decrease in the number of cluster headaches.

Migraine is thought to be a disease caused by dilation of cerebral bloodvessels. In animal studies, perivascular fibres of intracranial arterieshave been traced back to the SPG and stimulation of the SPG inducesdilatation of cranial blood vessels, plasma protein extravasation andrelease of inflammatory substances. Activation of parasympathetic fibrestraversing the SPG may be involved in migraine pathophysiology. In theSPG preganglionic parasympathetic fibres synapse with postganglionicfibres using acetylcholine as the neurotransmitter. BoNT causes neuralblock by inhibiting acetylcholine release and may therefore blockparasympathetic signaling through the SPG and hence inhibit perivascularrelease of neurotransmitters involved in migraine. Since sympathetic andsensory fibres do not synapse in the sphenopalatine fossa, it seemsreasonable to posit that synaptic transmission will not be affected. Noevent of numbness or paraesthesia distant from the injection site wasregistered. In both studies the author carefully chronicled all changesin the subjects, yet other than headache, the improvement in anysymptoms and conditions mentioned above after application of localanesthetic to the SPG were not seen.

In skin disorders, however, the pathophysiology differs. One theory foracne proposes that a neuropeptide called substance P plays an importantrole. Substance P has been implicated in pain, inflammation, sebaceoussecretions and epithelial hypertrophy. Many of these phenomena are seenin skin disorders. Substance P is not prominent in cholinergicparasympathetic neurons. Rather it is present in certain sensory neuronsand a poorly understood class of neurons called non-adrenergicnon-cholinergic.

In the head and neck there is a single sympathetic ganglion (superiorcervical ganglia) and four parasympathetic ganglia ciliary,sphenopalatine, submandibular and otic. Each ganglion is associated withand attached to one of the cranial nerves. The superior sympatheticganglia supplies all sympathetic innervation to the head. The fourparasympathetic ganglia are: 1. The ciliary ganglion carriesparasympathetic neurons with the 3rd cranial nerve (oculomotor) andsupplies innervation to the orbit. 2. The sphenopalatine ganglia (SPG)carries parasympathetic neurons from the 7th cranial nerve (facialnerve) and lies under the second division (maxillary branch) of the 5thcranial nerve (trigeminal) in the pterygopalatine fossa (PPF). Among itsfunctions it innervates a large area of the skin of the face. 3. Thesubmandibular ganglia also carries parasympathetic neurons from the 7thcranial nerve (facial nerve) and is located beneath and lateral to thetongue. It controls the production of saliva from the submandibular andsublingual glands. 4. The otic ganglion carries parasympathetic neuronsfrom the 9th cranial nerve (the glossopharyngeal) and hangs beneath thethird division of the trigeminal nerve (mandibular branch). The oticganglia innervates the skin in the lower face and neck.

Botulinum Neurotoxin

Botulinum toxins (BoNT) are potent poisons present in nature produced bythe anaerobic bacterium Clostridium botulinum and beratii. Sevenserotypes of toxins have been recognized, named as A through G.Recently, a novel toxin serotype was discovered and designated “H”,although its identity is controversial. The active BTX molecule consistsof two chains weighing ˜150,000 Daltons, in which a heavy chain islinked by a disulfide bond to a light chain. Each chain has specificaction; the former is responsible for neuron internalization, and thelight chain binds to a specific target protein involved in the dockingand fusion of acetylcholine-containing vesicles collectively referred toas the SNARE complex, which is responsible for vesicle acetylcholinerelease. BoNT-A cleaves a protein of the SNARE complex termed SNAP-25,blocking acetylcholine release. The derangement of this process atneuro-muscular junctions causes clinical effects consisting of muscleweakness and paralysis. To date, four formulations of BoNT-A are on themarket and used in clinical practice: onabotulinumtoxinA (Botox,Allergan, Inc., Irvine, Calif., USA), abobotulinumtoxinA (Dysport, IpsenLtd., Berkshire, UK), incobotulinumtoxinA (Xeomin, Merz, Frankfurt,Germany), and a Chinese toxin Prosigne (Lanzhou Institute, Lanzhou,China). The preparations differ in the process of production, theformulations and the potencies which are determined by differentbiological assays based on their clinical use. BoNT-B classified asrimabotulinumtoxinB, is commercially available and marketed by SolsticeNeuroscience (Malvern, Pa., USA) as MyoBloc in the United States andNeuroBloc (Elan Pharmaceuticals, San Diego, Calif., USA) in Europe. Itis important to note that the potency of a single unit is variable amongthe commercial formulations. The potency of 1 U of onabotulinumtoxinA(Botox) is about equal to 1 U of incobotulinumtoxinA (Xeomin), 3 U ofabobotulinumtoxinA (Dysport) and 40 to 50 U of rimabotulinumtoxinB(Neurobloc). However, it is very important to recognize that this ratioof equivalence cannot be employed. For injections, botulinum toxins typeA are diluted with 0.9% sodium chloride solution.

(a) General Considerations for BoNT Injection or Topical Application.

Injections are preferably made every 3-12 months or upon return ofsymptoms. The dose injected on one side can vary from about 0.1-1000units, preferably about 5-50 units, and more preferably about 20-30units for botulinum neurotoxin type A, for example onabotulinumtoxin A(Botox). In some instances and depending upon the type of botulinumneurotoxin used, the amount employed would increase, for example, forrimbotulinumtoxin B (Neurobloc) the amount administered would beapproximately 50-times the amount of botulinum neurotoxin relative toonabotulinum toxin A (botox), i.e., from about 5-50,000 units,preferably about 250-2500 units, and more preferably about 1000-1500units for botulinum neurotoxin type B. Injections can be unilateral orbilateral depending on the nature and location of the lesion. Injectionscan be done simultaneously on both sides or separately.

In another embodiment of this technique, an injection of epinephrine canprecede, or be given simultaneous or even after the BoNT injection. Theepinephrine contracts blood vessels, thereby decreasing the soft tissuevolume within the pterygopalatine fossa. It also aids in preventing orminimizing any bleeding in the fossa. In addition, it decreases theextracellular space and fluid exchange in the area, decreasing thespread of the toxin.

In another embodiment the local and systemic spread of toxin can beminimize, a non-limiting example being serotype B a used. Type B ismarketed in liquid form with preservation aided by an acidic pH of 5.6.This particular product is known for its pain on injection and forseemingly substantial systemic spread to autonomically innervatedstructures, a non-limiting example being the salivary glands whichdecreases salivation which the patient experiences as dry mouth. Tocombat these side effects, the type B BoNT solution may be combined withepinephrine described above. In the particular case of BoNT the acidicnature of the solution may cause inflammation with increased fluidrelease and uptake by local blood vessels. This increased fluid exchangecould remove BoNT type B from the area and allow it to enter thesystemic circulation. To minimize this, a basic solution to neutralizethe acid pH and decrease the acidic nature of the injection. Thisdecreases pain and the inflammation in the area.

The devised volumes are variable and depend on the planned dose that theclinician intends to inject. As it is preferable that the injection belocalized to thee target, small volumes of injection solution arepreferable (0.1 to 10 cc, preferably 0.5 to 1 cc). It is also preferablethat the BoNT is injected slowly, including about 10 seconds to hours,in some instances about 30 seconds to about an hour, in yet otherinstances about 30 seconds to about 10 minutes, in still other instancesabout 1 minute to about 5 minutes, preferably 1 minute. Long injectionsare possible by computer-controlled injection needles.

Depending on the experience of the physician and other factors,injections can be done with the physician using navigation aids inneedle placement. In intra nasal injection a rigid endoscope providesdirect visualization of the injection site, and/or the site for topicalmucosal application. Ct scans and or MRI imaging can be obtained to seethe anatomy of a proposed injection site in or to plan the injectionroute. Using CT scans a 3 dimensional model of the bony injection sitecan be made. Then the physician can plan exactly what injectionparameters he needs. A 3 dimensional guide could be manufactured to aidthe physician.

BoNT toxin can be injected to various targets with or without localmedication. The type of BoNT can differ, a non-limiting example beingthat BoNT type E, a short acting toxin that may be used to test theresponse of a skin lesion, or to provide temporary relief when somesymptoms flare up intermittently. These injections can be separated intime. Injection of each side can be done simultaneously, or theinjections may separated in time from days to months.

BoNT and other medications may be applied in various combinations. As anon-limiting example, the SPG can be injected by itself on one side,both sides, with another ganglia injection, and with a local applicationof BoNT or other medication to the lesions on the skin itself(topically, sub or intradermal). Non-limiting example of combinations oftherapy may include BoNT to the ganglia with or without localmedication, different BoNT preparations at various sites, BoNT and localmedication at the lesion site, systemic medication with or without BoNTor local medications.

Electrical stimulation can be used to help navigation. The tip of theneedle may have a monopolar or bipolar electrode. As the needleapproaches the SPG the subject feels sensation in the base of his noseand the medication is injected. Those familiar with clinical practiceart can readily envision variations on drug therapies known in the art.

(b) Sphenopalatine (SPG) Ganglia

The SPG is a non-limiting example of a ganglia. It is located in thepterygopalatine fossa (PPF) deep in the skull behind the maxillarysinus. Within the PPF the trigeminal nerve passes through supplyingsensory neurons to the face, sympathetic neurons pass through, andparasympathetic neurons synapse to their post ganglionic neurons whichare distributed throughout the head and neck.

BoNT can be applied by injection to the SPG ganglia in four differentways

(i) Zygomatic

In the suprazygomatic approach the patient is placed supine with thehead in a neutral position. The needle entry point is found at the angleformed by the superior edge of the zygomatic arch below and theposterior orbital rim forward. The needle (22 to 25 gauge) is insertedperpendicular to the skin and advanced to reach the greater wing of thesphenoid at a depth of approximately 10-15 mm). The needle is thenreoriented in a caudal and posterior direction and advanced a further35-45 mm to reach the pterygopalatine fossa. After a negative aspirationtest for blood, solution is slowly injected. Nerve stimulation may helplocate the pterygopalatine fossa: Nerve stimulation is associated withparesthesia coinciding with the stimulating frequency of the nervestimulator. In anesthetized children, stimulation of the temporal musclethat results in a mandibular contraction may be noted. The disappearanceof the muscle contraction heralds the passage through the temporalmuscle and entrance into the pterygomaxillary fossa. In an alternativeembodiment the needle can be inserted below the zygomatic arch(infrazygomatic).

(ii) Intranasal

Preferably the nose is decongested with phenylephrine or epinephrine andanesthetized with lidocaine. A flexible or rigid scope is passed intothe nasal cavity such that it visualizes the mucosa posterior to themiddle turbinate. A syringe contained BoNT diluted with preferably 1-4cc of normal saline is attached to a long needle preferably about 3.5 cmand preferably 27 gauge. The needle is introduced into the nasal cavityand advanced until the needle tip is at the posterior border of themiddle turbinate. The needle is then slowly advanced 1-10 mm throughmucosa behind the middle turbinate. The needle is aspirated and theninjection is made.

Topical intranasal administration may be done by saturating a cottonpledgets or other porous material and placing it into the nose such thatit lies against nasal mucosa. A cotton applicator or similar device canbe used to deliver more localized medication.

(iii) Palatal

The patient is placed supine and asked to open the mouth widely. Theexit of the pterygopalatine canal is identified on the hard palate aboutmid-way between the 2^(nd) or 3^(rd) molar and the midline. A needle isadvanced into the foramen in a posterosuperior direction at an angle of45-60 degrees from the horizontal plane of the hard palate. At 20-30 mmthe needle is aspirated and then injection is made.

(iv) High Tuberosity

A 25-gauge long needle is recommended for this injection, but a 27-gaugeis acceptable. The penetration site for the maxillary block is theheight of the mucobuccal fold distal to the maxillary second molar.Prior to placing topical anesthetic, it is important to use a finger tofeel along the facial aspect of the maxilla to find the zygomaticprocess, which is usually located above the first maxillary molar. It isimportant to insert distal to the zygomatic process or the maxillarybone may be scraped during administration. The angle of the syringeshould be 45° from the mid-sagittal plane, as well as 45° apically fromthe maxillary occlusal plane. A helpful visual guide for this angle is aline running from the lateral periphery of the ala of the nose to theinside corner of the opposite eyebrow. The average depth of penetrationfor the maxillary block is 30 mm. With a 32 mm long needle, 2 mm ofneedle should remain visible outside the tissue. The bone should not becontacted on this injection, and the needle should progress smoothlythrough the tissues. The clinician should know the exact length of theneedle, as different manufacturers produce different needle lengths. Ifboth aspirations are negative, the injection anesthetic should be slowlydeposited, re-aspirating every ¼ of the cartridge to make sure a bloodvessel has not been penetrated. The clinician should administer thisinjection slowly (taking more than 60 seconds to deliver the fullamount) because of the highly vascular nature of the pterygopalatinefossa.

EXAMPLES

The following examples are given for the purpose of illustrating variousembodiments of the invention and are not meant to limit the presentinvention in any fashion. The present examples, along with the methodsdescribed herein are presently representative of preferred embodiments,are exemplary, and are not intended as limitations on the scope of theinvention. Changes therein and other uses which are encompassed withinthe spirit of the invention as defined by the scope of the claims willoccur to those skilled in the art.

Example 1: Treatment of Acne

(i) 1A, Hard Palate Technique (Greater Palatine or PterygopalatineCanal).

A 16 year old girl has acne with continual blockheads on both cheekswith flareups of acne vulgaris with papules on her forehead and cheeks.Her physician reconstitutes 100 units BoNT with 4 cc of normal saline.The physician injects her SPG with 1 cc of solution using the palataltechnique. The exit of the pterygopalatine canal is identified on thehard palate about mid-way between the 2^(nd) or 3^(rd) molar and themidline. A cotton tip applicator with 4% lidocaine is applied to themucosa overlying the entrance of the pterygopalatine canal for 3minutes. A needle is advanced into the foramen in a posterosuperiordirection at an angle of 45-60 degrees from the horizontal plane of thehard palate. At 20-30 mm the needle is aspirated and then injection of 1cc (25 units) is made. The result is a 50% improvement in papule numbersand size within 2 weeks.

(ii) 1B. Zygomatic Techniques

In another embodiment, the same patient described in 1A above isinjected using the suprazygomatic approach. The patient is placed supinewith the head in a neutral position. The needle entry point is found atthe angle formed by the superior edge of the zygomatic arch below andthe posterior orbital rim forward. The needle (22 to 25 gauge) isinserted perpendicular to the skin and advanced to reach the greaterwing of the sphenoid at a depth of approximately 10-15 mm). The needleis then reoriented in a caudal and posterior direction and advanced afurther 35-45 mm to reach the pterygopalatine fossa. After a negativeaspiration test for blood, solution is slowly injected. Nervestimulation may help locate the pterygopalatine fossa: Nerve stimulationis associated with paresthesia coinciding with the stimulating frequencyof the nerve stimulator. In anesthetized children, stimulation of thetemporal muscle that results in a mandibular contraction may be noted.The disappearance of the muscle contraction heralds the passage throughthe temporal muscle and entrance into the pterygomaxillary fossa.

In another embodiment the procedure is performed under x-rayvisualization (Fluoroscopy). In this technique an x-ray machine canprovide real time continuous x-ray images of the bony skull. The needletip can then be visualized to be in the proper position prior toinjection.

In an alternative embodiment the needle can be inserted below thezygomatic arch (infrazygomatic approach). In this technique the needleis inserted underneath the zygomatic arch.

(iii) 1C. High Tuberosity Approach.

In another embodiment the high tuberosity method is used. A 25-gaugelong needle is recommended for this injection, but a 27-gauge isacceptable. The penetration site for the maxillary block is the betweenthe upper lip and the upper maxillary teeth. Prior to placing topicalanesthetic, it is important to use a finger to feel along the facialaspect of the maxilla to find the zygomatic process, which is usuallylocated above the first maxillary molar. It is important to insertdistal to the zygomatic process or the maxillary bone may be scrapedduring administration. The angle of the syringe should be 45° from themid-sagittal plane, as well as 45° apically from the maxillary occlusalplane. A helpful visual guide for this angle is a line running from thelateral periphery of the ala of the nose to the inside corner of theopposite eyebrow. The average depth of penetration for the maxillaryblock is 30 mm. With a 32 mm long needle, 2 mm of needle should remainvisible outside the tissue. The bone should not be contacted on thisinjection, and the needle should progress smoothly through the tissues.The clinician should know the exact length of the needle, as differentmanufacturers produce different needle lengths. If both aspirations arenegative, the injection anesthetic should be slowly deposited,re-aspirating every ¼ of the cartridge to make sure a blood vessel hasnot been penetrated. The clinician should administer this injectionslowly (taking more than 60 seconds to deliver the full amount) becauseof the highly vascular nature of the pterygopalatine fossa.

(iv) 1D. Intranasal

The patient lies with the side of the head to be injected horizontal tothe floor. If decongestion or anesthesia is needed, 1% lidocaine withepinephrine 1:100,000 is applied. 1-4 cc are placed on a cotton pledgetthat is placed into the nasal cavity for 15 minutes, or one or bothmedication can also be sprayed. After decongestion and anesthesia isobtained a 2-5 mm rigid or flexible endoscope is placed into the nostriland advanced backward to visualize the nasal cavity. A 5 inch needlewith a ¼ inch curve is inserted into the nasal cavity and advance intothe nasal cavity. The tip of the needle is then seen by the endoscope.The needle then is pushed through the mucosa over the sphenopalatineforamen and the advanced 5-10 mm further. A 0.5 cc solution of 50 unitsBoNT is slowly injected over 2 minutes. After injection the patient isinstructed to lie in the same position for an additional 30 minutes.

In another embodiment the 50 nits of BoNT solution is saturate onto acotton applicator. With a scope in place the applicator is advancedslowly backward in the nose until reaching the area behind the middleturbinate. The applicator is placed against the mucosa for 1 hour.

(v) 1E. Combined Therapy

The patient experiences a flare up of her acne despite being one monthafter her botulinum neurotoxin injection. The physician notes bilateralblackheads on on both cheeks with some cystic lesions He diagnosescomedone acne with an acne vulgaris component. A course of topicalTretinoin cream 0.05% is prescribed to be applied twice a day to theaffected area. In addition, a ten day course of the antibiotic oraltetracycline is prescribed. After two weeks most of the comedone havedisappeared but there is only a 50% improvement in thee acne vulgariscystic lessons. The physician then injects 0.1 c of a 1 cc solutioncontaining 100 units of BoNT. Each injection is made intradermallydirectly next to a cystic lesion. After 2 weeks the patient has completeresolution of her acne vulgaris. Due to the good response to intradermalBoNT she is placed on a regimen of intradermal injections every 3 monthswith oral and topical medications added during flareups.

Example 2: Eczema

A 40-year-old female has eczema on her scalp. Her physicianreconstitutes 100 units in 2 ccc of normal saline. The nose isdecongested with 1:100,000 phenylephrine or epinephrine and anesthetizedwith 1% lidocaine. A flexible or rigid scope is passed into the nasalcavity such that it visualizes the mucosa posterior to the middleturbinate. A syringe contained BoNT diluted with 1 cc of normal salineis attached to a long needle preferably about 3.5 cm and preferably 27gauge. The needle is introduced into the nasal cavity and advanced untilthe needle tip is at the posterior border of the middle turbinate. Theneedle is then slowly advanced 5 mm through mucosa behind the middleturbinate. The needle is aspirated and then a 0.25 cc injection is madeslowly over 1 minute. When seen in 1 week the eczema has completelyresolved.

Example 3: Seborrhea

All variations of seborrhea diseases as described above are alternativeembodiments: seborrheic dermatitis, rhinophyma, and sebaceous cysts.Infectious conditions related to excessive holocrine secretions includehidradenitis, furuncles, carbuncles, styes, chalazions and horboleum.

A 40-year-old male has seborrheic dermatitis on his scalp. His physicianreconstitutes 100 units in 2 cc of normal saline. The nose isdecongested with 1:100,000 phenylephrine or epinephrine and anesthetizedwith 1% lidocaine. A flexible or rigid scope is passed into the nasalcavity such that it visualizes the mucosa posterior to the middleturbinate. A syringe contained BoNT diluted with 1 cc of normal salineis attached to a long needle preferably about 3.5 cm and preferably 27gauge. The needle is introduced into the nasal cavity and advanced untilthe needle tip is at the posterior border of the middle turbinate. Theneedle is then slowly advanced 5 mm through mucosa behind the middleturbinate. The needle is aspirated and then a 0.25 cc injection is madeslowly over 1 minute. When seen in 1 week the seborrheic dermatitis hascompletely resolved.

Example 4: Psoriasis

A 30-year-old female has a 4 cm×6 cm patch of psoriasis on the back ofher neck. Her physician reconstitutes 100 units of Dysport with 2 cc ofnormal saline and is drawn into a 5-cc syringe. A 25-gauge 3.5-inchneedle is attached to the syringe. Using his finger the facial aspect ofthe maxilla is palpated to find the zygomatic process, the needle isthen inserted distal to the zygomatic process. The needle is introducedinto the mucobuccal fold distal to the maxillary second molar. The angleof the syringe should be 45° from the mid-sagittal plane, as well as 45°apically from the maxillary occlusal plane. A helpful visual guide forthis angle is a line running from the lateral periphery of the ala ofthe nose to the inside corner of the opposite eyebrow. The average depthof penetration for the maxillary block is 30 mm. With a 32 mm longneedle, 2 mm of needle should remain visible outside the tissue. Thebone should not be contacted on this injection, and the needle shouldprogress smoothly through the tissues. If aspirations are negative, theinjection of 1 cc (50 units) should be slowly deposited, re-aspiratingevery ¼ of the cartridge to make sure a blood vessel has not beenpenetrated. The clinician should administer this injection slowly(taking more than 60 seconds to deliver the full amount) because of thehighly vascular nature of the pterygopalatine fossa. Injection is thenmade to the opposite side. When seen by the physician at 1 week thepsoriasis lesion has shrunk by 50%, then 80% by the second week. Theeffect lasts for 1 year.

Example 5: Rosacea

A 40-year-old male has a rosacea involving both cheeks. The physicianreconstitutes 100 units of Botox with 4 cc of normal saline. The exit ofthe pterygopalatine canal is identified on the hard palate about mid-waybetween the 2^(nd) or 3^(rd) molar and the midline. A needle is advancedinto the foramen in a posterosuperior direction at an angle of 45-60degrees from the horizontal plane of the hard palate. At 20-30 mm theneedle is aspirated and then injection is made over 1 minute. A secondinjection is made on the opposite side. The rosacea completely resolvesover 1 month.

Example 6: Skin Smoothing

60 year old female is concerned by the rough texture, large skin poresand wrinkles of her facial skin. Her physician reconstitutes 100 unitsof Xeomin in 2 cc of normal saline. The nose is decongested with1:100,000 phenylephrine or epinephrine and anesthetized with 1%lidocaine. A flexible or rigid scope is passed into the nasal cavitysuch that it visualizes the mucosa posterior to the middle turbinate. Asyringe contained BoNT diluted with 1 cc of normal saline is attached toa long needle preferably about 5 cm and preferably 27 gauge. The needleis introduced into the nasal cavity and advanced until the needle tip isat the posterior border of the middle turbinate. The needle is thenslowly advanced 5 mm through mucosa behind the middle turbinate. Theneedle is aspirated and then a 1 cc injection is made slowly over 1minute. Then the opposite side is injected with the same amount. Whenseen in 1 month the skin is notable smoother with smaller skin pores andhas less prominent wrinkling.

Example 7: Oily Skin

A 40 year old female complains of oily skin which she finds sociallyunacceptable. She does not want multiple injections into her face. Thephysician lies the patient supine and anesthetizeds the mucosa above theforamen with topical anesthetic. After 2 minutes he inserts a 30 mm 29gauge needle through the greater palatine canal to a depth of 25 mm andinjects 0.5 cc of a solution containing 25 units of BoNT. The sameinjection is repeated on the opposite side. The patient is instructed toremain in the same position for 30 minutes. One week later the patientreturns and reports that her oily skin problem has resolved.

Bratbak D F, Nordgård S, Stovner L J, Linde M, Dodick D W, Aschehoug,Folvik, Tronvik E. Pilot study of sphenopalatine injection ofonabotulinumtoxinA for the treatment of intractable chronic migraine.Cephalalgia. 2017 April; 37(4):356-364. doi: 10.1177/0333102416648328.Epub 2016 May 6.

Bratbak DF1, Nordgård S2, Stovner LJ3, Linde M4, Folvik M5, Bugten V2,Tronvik E4. Cephalalgia. Pilot study of sphenopalatine injection ofonabotulinumtoxinA for the treatment of intractable chronic clusterheadache. 2016 May; 36(6):503-9. doi: 10.1177/0333102415597891. Epub2015 Jul. 31

DasGupta, B. R. Structures of botulinum neurotoxin, its functionaldomains and perspectives on the crystalline tipe A toxin. In Therapywith Botulinum Toxin; Jankovic, J., Hallet, M., Eds.; Marcel Dekker: NewYork, N.Y., USA, 1994; pp. 15-39.

Dressler, D. Routine use of Xeomin in patients previously treated withBotox: Long term results. Eur. J. Neurol. 2009, 16 (Suppl. S2), 2-5

Schiavo, G.; Benfenati, F.; Poulain, B.; Rossetto, O.; Polverino deLaureto, P.; DasGupta, B. R.; Montecucco, C. Tetanus and boulinum-Bneurotoxin block neurotransmitter release by a proteolytic cleavage ofsynapto-brevin. Nature 1992, 359, 832-835.

Benecke, R.; Jost, W. H.; Kanovsky, P.; Ruzicka, E.; Comes, G.; Grafe,S. A new botulinum toxin type A free of complexing proteins fortreatment of cervical dystonia. Neurology 2005, 64, 1949-1951.

Dressler, D. Routine use of Xeomin in patients previously treated withBotox: Long term results. Eur. J. Neurol. 2009, 16 (Suppl. S2), 2-5

Malamed S. Handbook of Local Anesthesia. 6th ed. St. Louis: ElsevierMosby; 2013

Malamed S. Handbook of Local Anesthesia. 6th ed. St. Louis: ElsevierMosby; 2013

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of treating skin disorders comprisingapplying a therapeutically effective amount of botulinum neurotoxin tonerve ganglia.
 2. The method of claim 1, wherein the nerve ganglia is aparasympathetic nerve ganglia.
 3. The method of claim 1, wherein thenerve ganglia is a sphenopalatine ganglia, a ciliary ganglia, asubmandibular ganglia, superior cervical ganglia, trigeminal ganglia,stellate ganglia and/or an otic ganglia.
 4. The method of claim 1,wherein the nerve ganglia is a sphenopalatine ganglia.
 5. The method ofclaim 4, wherein the botulinum neurotoxin is applied to apterygopalatine fossa.
 6. The method of claim 1, wherein the botulinumneurotoxin is applied to the sphenopalatine ganglia.
 7. The method ofclaim 6, wherein the botulinum neurotoxin is applied zygomatically,intranasally, through a hard palate technique, using a high tuberosityapproach or combinations thereof.
 8. The method of claim 1, wherein theskin disorder is chosen from the group consisting of acne, eczema,psoriasis, seborrhea, rosacea and combinations thereof.
 9. The method ofclaim 1, wherein the botulinum neurotoxin is chosen from the groupconsisting of botulinum neurotoxin type A, botulinum neurotoxin type B,botulinum neurotoxin type C, botulinum neurotoxin type D, botulinumneurotoxin type E, botulinum neurotoxin type F, botulinum neurotoxintype G, and combinations thereof.
 10. The method of claim 1, wherein thebotulinum neurotoxin is botulinum neurotoxin type A.
 11. The method ofclaim 1, wherein the botulinum neurotoxin is botulinum neurotoxin typeB.
 12. The method of claim 11, wherein the botulinum neurotoxin type Bis administered with epinephrine.
 13. The method of claim 11, whereinthe botulinum neurotoxin type B further comprises a basic solution. 14.The method of claim 1, wherein the amount of botulinum neurotoxinadministered is between about 0.1 to about 1000 units.
 15. The method ofclaim 1, wherein the amount of botulinum neurotoxin administered isbetween about 5 to about 50 units.
 16. The method of claim 1, whereinthe botulinum neurotoxin is administered over a period of time.
 17. Themethod of claim 1, wherein the botulinum neurotoxin is administered overone minute.
 18. The method of claim 1, wherein the volume of botulinumneurotoxin administered is between 0.1 to 10 cc.
 19. The method of claim1, wherein the botulinum neurotoxin is further administered locally tothe skin.
 20. A method of smoothing skin and reducing wrinkles in skin,the method comprising applying a therapeutically effective amount ofbotulinum neurotoxin to nerve ganglia.
 21. The method of claim 20,wherein the nerve ganglia is a parasympathetic nerve ganglia.
 22. Themethod of claim 20, wherein the nerve ganglia is a sphenopalatineganglia, a ciliary ganglia, a submandibular ganglia, superior cervicalganglia, trigeminal ganglia, stellate ganglia and/or an otic ganglia.23. The method of claim 20, wherein the nerve ganglia is asphenopalatine ganglia.
 24. The method of claim 23, wherein thebotulinum neurotoxin is applied to a pterygopalatine fossa.
 25. Themethod of claim 20, wherein the botulinum neurotoxin is applied to thesphenopalatine ganglia.
 26. The method of claim 25, wherein thebotulinum neurotoxin is applied zygomatically, intranasally, through ahard palate technique, using a high tuberosity approach or combinationsthereof.
 27. The method of claim 20, wherein the skin pore size isreduced.
 28. The method of claim 20, wherein the botulinum neurotoxin ischosen from the group consisting of botulinum neurotoxin type A,botulinum neurotoxin type B, botulinum neurotoxin type C, botulinumneurotoxin type D, botulinum neurotoxin type E, botulinum neurotoxintype F, botulinum neurotoxin type G, and combinations thereof.
 29. Themethod of claim 20, wherein the botulinum neurotoxin is botulinumneurotoxin type A.
 30. The method of claim 20, wherein the botulinumneurotoxin is botulinum neurotoxin type B.
 31. The method of claim 30,wherein the botulinum neurotoxin type B is administered withepinephrine.
 32. The method of claim 30, wherein the botulinumneurotoxin type B further comprises a basic solution.
 33. The method ofclaim 20, wherein the amount of botulinum neurotoxin administered isbetween about 0.1 to about 1000 units.
 34. The method of claim 20,wherein the amount of botulinum neurotoxin administered is between about5 to about 50 units.
 35. The method of claim 20, wherein the botulinumneurotoxin is administered over a period of time.
 36. The method ofclaim 20, wherein the botulinum neurotoxin is administered over oneminute.
 37. The method of claim 20, wherein the volume of botulinumneurotoxin administered is between 0.1 to 10 cc.
 38. The method of claim1, wherein the botulinum neurotoxin is further administered locally tothe skin.
 39. A method of treating skin infections related to excessiveholocrine secretions comprising applying a therapeutically effectiveamount of botulinum neurotoxin to nerve ganglia.
 40. The method of claim39, wherein the nerve ganglia is a parasympathetic nerve ganglia. 41.The method of claim 39, wherein the nerve ganglia is a sphenopalatineganglia, a ciliary ganglia, a submandibular ganglia, superior cervicalganglia, trigeminal ganglia, stellate ganglia and/or an otic ganglia.42. The method of claim 39, wherein the nerve ganglia is asphenopalatine ganglia.
 43. The method of claim 42, wherein thebotulinum neurotoxin is applied to a pterygopalatine fossa.
 44. Themethod of claim 39, wherein the botulinum neurotoxin is applied to thesphenopalatine ganglia.
 45. The method of claim 44, wherein thebotulinum neurotoxin is applied zygomatically, intranasally, through ahard palate technique, using a high tuberosity approach or combinationsthereof.
 46. The method of claim 39, wherein the excessive holocrinesecretion condition is chosen from the group consisting of hidradenitis,furuncles, carbuncles, styes, chalazions, horoleum and combinationsthereof.
 47. The method of claim 39, wherein the botulinum neurotoxin ischosen from the group consisting of botulinum neurotoxin type A,botulinum neurotoxin type B, botulinum neurotoxin type C, botulinumneurotoxin type D, botulinum neurotoxin type E, botulinum neurotoxintype F, botulinum neurotoxin type G, and combinations thereof.
 48. Themethod of claim 39, wherein the botulinum neurotoxin is botulinumneurotoxin type A.
 49. The method of claim 39, wherein the botulinumneurotoxin is botulinum neurotoxin type B.
 50. The method of claim 49,wherein the botulinum neurotoxin type B is administered withepinephrine.
 51. The method of claim 49, wherein the botulinumneurotoxin type B further comprises a basic solution.
 52. The method ofclaim 39, wherein the amount of botulinum neurotoxin administered isbetween about 0.1 to about 1000 units.
 53. The method of claim 39,wherein the amount of botulinum neurotoxin administered is between about5 to about 50 units.
 54. The method of claim 39, wherein the botulinumneurotoxin is administered over a period of time.
 55. The method ofclaim 39, wherein the botulinum neurotoxin is administered over oneminute.
 56. The method of claim 39, wherein the volume of botulinumneurotoxin administered is between 0.1 to 10 cc.
 57. The method of claim39, wherein the botulinum neurotoxin is further administered locally tothe skin.